26 HbA1c változás: 82 hetes interim eredményekPlacebo-kontrollNyílt kiterjesztés0.5Kiindulási HbA1cPlacebo BID (n = 69)8.2%5 mg exenatid BID (n = 69)8.3%DISCUSSION:Exenatide treatment resulted in sustained mean HbA1c reductions from baseline, with a decrease of -1.0% at 82 weeks.Placebo cohort upon receiving exenatide (at Week 30) showed an immediate decrease of HbA1c similar to that observed with exenatide treatment in the first 30 weeks.The slight upward trend seen for both the placebo and exenatide treatment groups from Weeks 18 to 30 likely represents an initial study effect that disappears over time, and is similar in magnitude to the decrease in HbA1c during the 4-week placebo lead-in period.STUDY BACKGROUND:Interim results from subjects who completed one of the three 30-week pivotal trials (with a background of MET and SFU) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extension for a total of 82 weeks of treatment (n=205).Subjects are grouped by the treatment to which they were originally randomized in the placebo-controlled trial, with the increase to 10 g in the extension indicated with an arrow: placebo BID (placebo10 g), 5 g BID (5 g 10 g), 10 g BID (10 g 10 g).All subjects were given 5 g exenatide for the first 4 weeks of the open-label extension (overall, Weeks 30 to 34), after which they received 10 g exenatide.0.010 mg exenatid BID (n = 67)8.5%D HbA1c (%)-0.5-1.0 ± 0.1%-1.0-1.0 ± 0.2%-1.0 ± 0.2%-1.5102030405060708090Idő (hét)Ratner, RE et al: Diab Obes Metab 8:Blonde, L et al : Diab Obes Metab 8:Mean (SE)

27 Testsúly változás: 82 hetes interim eredményekPlacebo-kontrollNyílt kiterjesztésKiindulási súlyPlacebo BID (n = 69)97.6 kg5 mg exenatid BID (n = 69)97.4 kgDISCUSSION:Exenatide treatment resulted in progressive mean weight reductions from baseline, with a decrease of -3.9 to -4.4 kg at 82 weeks.Placebo cohort upon receiving exenatide showed an immediate decrease of weight similar to that observed with exenatide treatment in the first 30 weeks.No diet and/or exercise counseling provided by the protocol.STUDY BACKGROUND:Interim results from subjects who completed one of the three 30-week pivotal trials (with a background of MET and SFU) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extension for a total of 82 weeks of treatment (n=205).Subjects are grouped by the treatment to which they were originally randomized in the placebo-controlled trial, with the increase to 10 g in the extension indicated with an arrow: placebo BID (placebo10 g), 5 g BID (5 g 10 g), 10 g BID (10 g 10 g)All subjects were given 5 g exenatide for the first 4 weeks of the open-label extension (overall, Weeks 30 to 34), after which they received 10 g exenatide.10 mg exenatid BID (n = 67)99.5 kg-1-2D Testsúly (kg)-3-4.0 ± 0.5 kg-4-3.9 ± 0.6 kg-4.4 ± 0.5 kg-5102030405060708090Idő (hét)Ratner, RE et al: Diab Obes Metab 8:Mean (SE)

28 Keringési kockázati tényezők alakulása I. : a vérnyomás változása a 82Keringési kockázati tényezők alakulása I.: a vérnyomás változása a 82. héten testsúly kvartilisek szerinti bontásbanSystolés BPDiastolés BP624DISCUSSION:A majority of subjects had both systolic and diastolic blood pressure (BP) improvementsWhen analyzed by quartile, only those subjects in quartile 4 did not have decreased BPThese reductions occurred even in the context of relatively low baseline BP (mean = 129/79).STUDY BACKGROUND:Interim results from subjects who completed the 30-week pivotal trials (5 g and 10 g arms, not placebo) and completed an additional 52 weeks of exenatide treatment in the corresponding open-label extensions for a total of 82 weeks of exenatide (n=265).Quartiles consisted of four subgroups with approximately equal number of subjects (n=66-67), with quartile 1 consisting of the 25% of subjects with the greatest weight reductions, quartile 4 consisting of the 25% of subjects with the smallest weight reductions (or weight gains), and quartiles 2 and 3 are for those with the intermediate weight reductions. These same quartiles are used in portraying BP changes.+3.00.02D BP (Hgmm )D BP (Hgmm)-2-2-2.6-3.0-4.1-3.3-4-4.4-4.5-4-6-6IIIIIIIVIIIIIIIVTestsúly kvartilisTestsúly kvartilisBlonde, L et al.: Diab Obes Metab 8:n=265; Mean (SE)

29 Serum HDL-koleszterinKeringési kockázati tényezők alakulása II.: a serum triglicerid és HDL-chol. 82. heti változása testsúly kvartilisek szerinti bontásbanSerum trigliceridSerum HDL-koleszterin2010-3+78DISCUSSION:Triglycerides (TG) decreased in the two quartiles of patients that had the greatest weight reductions.High-density lipoprotein (HDL)-C increased in all 4 quartiles, most dramatically in quartile 1.Both HDL and TG changes were clinically significant.STUDY BACKGROUND:Interim results from subjects who completed the 30-week pivotal trials (5 g and 10 g arms, not placebo) and completed an additional 52 weeks of exenatide treatment in the corresponding open label extensions for a total of 82 weeks of exenatide (n=265).Quartiles consisted of four subgroups with approximately equal number of subjects (n=66-67), with quartile 1 consisting of the 25% of subjects with the greatest weight reductions, quartile 4 consisting of the 25% of subjects with the smallest weight reductions (or weight gains), and quartiles 2 and 3 are for those with the intermediate weight reductions. These same quartiles are used in portraying lipid changes.-20+7.46-40D (mg/dl)-58D (mg/dl)-604+3.8-80+3.5-92+3.02-100-120IIIIIIIVIIIIIIIVTestsúly kvartilisTestsúly kvartilisn=265; átlag ± SEBlonde, L et al.: Diab Obes Metab 8:

31 A HbA1c alakulása a vizsgálatbanExenatid, 10 mg naponta 2xGlargin inzulin, átl.dózis a kezelés végén = 25.0 U/nap12260.06.57.07.58.08.5DISCUSSION:HbA1c was measured at screening (Week -4), baseline (Week 0), Week 12, Week 26 (endpoint) and, if possible, at the time of discontinuation for those who dropped out of the study before completion of Week 26.Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients.HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%).The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%.STUDY BACKGROUND:At endpoint, the average dose of insulin glargine was 25.0 IU/day (n = 244). 21.6% of insulin glargine patients, compared with 8.6% of exenatide patients, achieved a fasting glucose of <5.6 mmol/L (100 mg/dL).The daily insulin dose achieved in the present study is lower when compared to other published large-scale randomized clinical trials of insulin glargine (Riddle et al, Diabetes Care. 2003; Benedetti et al, Horm Metab Res 2003; Fritsche et al, Ann Intern Med 2003; Rosenstock et al, Diabetes Care 2001; Yki-Jarvinen et al, Diabetes Care 2000). However, in the present study, the baseline HbA1c was lower than each of those previous trials, possibly resulting in less insulin required to attain a certain glycemic improvement, and all patients entered this trial already taking two oral agents. The mean reduction in HbA1c in the present trial was within the range of reductions observed in previous insulin glargine trials with comparable study designs (ranging from -0.4 to -1.0% for weeks), except the Treat-to-Target trial (-1.65% at 24 weeks) (Riddle et al, Diabetes Care. 2003).In the Treat-to-Target trial, Riddle et al described a number of factors to explain the magnitude of the HbA1c decrease observed, including an ambitious titration target combined with a protocol for encouraging patient adherence. Although problematic to compare across trials, the Treat-to-Target trial also reported a higher incidence of symptomatic (13.9 events per year) and nocturnal hypoglycemia (4.0 events per year) and slightly greater weight gain (+3.0 kg) than observed in the present trial. Moreover, the mean HbA1c achieved at study endpoint in the Treat-to-Target trial (6.96%) was not greatly different from the mean value achieved in the current study (7.12%), and the proportion of patients achieving HbA1c 7% was 58% (Treat-to-Target) versus 48% (present study).Two recently published trials have demonstrated very favorable results adding insulin glargine to patients receiving metformin and/or combination oral therapy (Janka et al, Diabetes Care, 2005 and Raskin et al, Diabetes Care 2005). However the study designs of these trials included the addition of new sulfonylurea therapy (Janka) or the discontinuation of some oral therapies during a run-in period (Raskin), making a direct comparison of these trial results somewhat difficult to interpret.The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine.Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable.HbA1c (%)HétBlonde, L et al.: Diab Obes Metab 8:ITT population; Mean ± SE shown

32 Betegek aránya, akik elértékA HbA1c változásaExenatidInzulin glargin46%48%32%25%102030405060-1.1%-1.5-1.0-0.50.0DISCUSSION:Eight patients in each group discontinued without a post-baseline measurement of HbA1c. Thus, the intent-to-treat sample is made up of 275 exenatide and 260 insulin glargine patients.HbA1c was significantly reduced from baseline at Week 26 in both treatment arms (change from baseline to endpoint, exenatide: ± 0.059%, insulin glargine: ± 0.058%).The 95% CI for the difference between treatments (exenatide–insulin glargine) was % to 0.157%. This is within the non-inferiority criteria of the upper limit <0.4%.A similar percentage of patients reached the HbA1c goal of <7% for each treatment. Proportion of patients to <6.5% were 31% for exenatide and 24% for insulin glargine.STUDY BACKGROUND:A meta-analysis of phase 3/3b controlled trials comparing insulin glargine to NPH insulin in 1142 adults with type 2 diabetes, including the Treat-to-Target study, reported an average HbA1c change associated with insulin glargine from a baseline of 8.8 ± 1.1% to 7.8 ± 1.3% (mean ± SD, trial endpoints ranged from weeks). [Rosenstock et al, Diabetes Care, 2005.]The insulin glargine titration schedule and approach to encouraging patient adherence in the present trial may have been more reflective of real-world usage; as a result, the data (~1% lowering) may better indicate the broader clinical experience with insulin glargine.Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable. For % to HbA1c <7%, ITT comprised patients with HbA1c >7% at baseline, and at least one post-baseline measurement of the dependent variableBetegek aránya, akik elértéka cél HbA1c értéket (%)Change in HbA1c (%)ITT populatio; átlag ± SEHbA1c<7%HbA1c<6.5%Blonde, L et al.: Diab Obes Metab 8:

33 Testsúlyváltozás (fontban)A testsúly változásaExenatidGlargin inzulin*248121826-6-4-26DISCUSSION:Insulin glargine patients gained weight throughout the trial period, while exenatide was associated with progressive reductions in weight.Mean body weight was significantly different between the two treatments as early as 2 weeks, and this difference persisted throughout the study.Adjusted mean change in body weight at endpoint was -5.1 ± 0.4 lbs for exenatide, +4.0 ± 0.4 lbs for insulin glargine.Mean difference (exenatide - insulin glargine) was -9.0 lbs, 95% CI for the difference -10.1, -7.7 lbs.Baseline body weights were exenatide: 87.5 ± 16.9 kg and insulin glargine: 88.3 ± 17.9 kg.Enhancing insulin secretion in the absence of weight gain is an important aspect of the incretin mimetics, and may represent an important therapeutic advance in the treatment of type 2 diabetes.STUDY BACKGROUND:Intent-to-treat sample was defined as any randomized patient who had at least one post-baseline measurement of the dependent variable.Testsúlyváltozás (fontban)Idő (hét)ITT populatio; Átlag ± SE; * P<0.0001, exenatid vs inzulin glargin azonos időpontban értékelveBlonde, L et al.: Diab Obes Metab 8:

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